Understanding mechanisms leading to decrements in lung function, the physiologic hallmark of obstructive lung diseases including chronic obstructive pulmonary disease (COPD), are necessary to inform interventions to improve lung health. In this application, we propose to examine the role of the antimicrobial peptide cathelicidin, and its primary regulator vitamin D, in lung function impairment, respiratory infections and acute exacerbations of COPD as well as evaluate the effect of oral vitamin D supplementation on lung cathelicidin levels in humans. Cathelicidin has bactericidal and inflammatory activities in the lung and is regulated by vitamin D levels. Our hypothesis is that reduced cathelicidin levels are associated with accelerated lung function decline though a pathway partially mediated by increased infections and COPD exacerbations. We hypothesize the effect of cathelicidin on lung function is greater in those with vitamin D insufficiency and that oral vitamin D supplementation will raise cathelicidin levels in the pulmonary compartment, thereby restoring lung cathelicidin deficiency. Specifically, through longitudinal investigation nested within an ongoing cohort study of urban, predominantly African-American individuals at high risk for development of OLDs, we will characterize the rate of lung function decline in 380 participants followed with serial spirometry measures for up to six years. Baseline and repeated measures of cathelicidin and vitamin D will be examined as independent predictors of lung function decline and respiratory infections. Separately, using longitudinal data from 2100 participants enrolled in the Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS) study with established COPD, baseline measures of blood cathelicidin and vitamin D will be examined as an independent predictor of longitudinal FEV1 decline and COPD exacerbations over three years. In both cohorts, concurrent vitamin D measurements will permit evaluation of antecedent and modifier on the cathelicidin-lung outcomes relationships. Finally, we will measure blood and lung lavage cathelicidin levels in 40 vitamin D insufficient individuals before and after eight weeks of oral vitamin D supplementation to determine the effect of vitamin D supplementation on cathelicidin levels. Completion of these aims will provide a robust determination of the role of cathelicidin in lung function decline and adverse pulmonary outcomes in unique populations of at-risk and diseased individuals. Moreover, the aims of this application directly or indirectly wor towards ultimately understanding if a readily measurable blood marker, cathelicidin, can inform who may benefit from vitamin D supplementation to prevent chronic lung disease. The results from this application would lead to a therapeutic intervention study that will provide further opportunities to improve our understanding of the relationship between vitamin D, cathelicidin and lung function.